Safety and Efficacy of Whole Brain LDRT+ICI+Intrathecal Chemotherapy in Refractory Meningeal Metastasis of Lung Cancer

NCT06431685 | Recruiting Phase 1

• 1 other identifier: LM-001
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I study aims to investigate the safety and efficacy of whole brain low dose radiotherapy (WB-LDRT) combined with ICI and intrathecal chemotherapy for treatment of refractory meningeal metastasis of lung cancer.

Conditions

NSCLC; Low Dose Radiotherapy; PD-1 Inhibitor; Leptomeningeal Metastasis

Outcome Measures

Primary Outcomes (2)

• Clinical response rate

  The RANO proposal for response criteria of leptomeningeal metastasis was used to assess the clinical response in this study.

  48 months

• Incidence of treatment-related adverse events

  The incidence of treatment-related adverse events were measured for determing tolerability and safety. Adverse events (AEs) are evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). Events of grade 3-5 are defined as moderate and severe adverse events.

  48 months

Secondary Outcomes (2)

• Neurological progression-free survival (NPFS)

  48 months

• Overall survival

  48 months

Study Arms (1)

whole brain LDRT + ICI + intrathecal chemotherapy

EXPERIMENTAL

The treatment regimen consisted of intrathecal chemotherapy (via lumbar puncture, pemetrexed 30 mg, once per three weeks, 4 cycles in total), PD-1 inhibitor (Sintilimab, via intravenous infusion, once per three weeks, 4 cycles in total)), pemetrexed chemotherapy (via intravenous infusion, once per three weeks, 4 cycles in total) and radiotherapy. Whole brain LDRT will be administered at 3 cohorts with increasing dose fractions: 4 Gy/2f of 2 fraction (administered a daily dose of 2 Gy for two days) in group 1; 4 Gy/2f of 4 fractions (administered a daily dose of 2 Gy for two days, once per three weeks, 2 cycles in total) in group 2; 4 Gy/2f of 8 fractions (administered a daily dose of 2 Gy for two days, once per three weeks, 4 cycles in total) in group 3.

Radiation: Whole Brain Low Dose Radiotherapy; Drug: Pemetrexed; Drug: Sintilimab; Drug: Chemotherapy

Interventions

Whole Brain Low Dose Radiotherapy RADIATION

Whole brain LDRT will be administered at 3 cohorts with increasing dose fractions: Group 1: 4 Gy/2f of one cycle; Group 2: 4 Gy/2f of two cycles (Q3w); Group 3: 4 Gy/2f of three cycles (Q3w). WB-LDRT will be administered in a 4 Gy of 2 fractions over two days, starting from Day 1 in the first cycle (a daily dose of 2 Gy, 4 Gy/2f for one cycle, once per three weeks, at minmum in one cycle and maximum in four cycles in total).

Also known as: WB-LDRT

whole brain LDRT + ICI + intrathecal chemotherapy

Pemetrexed DRUG

Pemetrexed, 30 mg, intrathecal injection, once per three weeks, 4 cycles in total

Also known as: Intrathecal Chemotherapy

whole brain LDRT + ICI + intrathecal chemotherapy

Sintilimab DRUG

PD-1 inhibitor (Sintilimab, dose as recommended in the instruction manual), intravenous infusion, once per three weeks, 4 cycles in total

Also known as: PD-1 Inhibitor

whole brain LDRT + ICI + intrathecal chemotherapy

Chemotherapy DRUG

Pemetrexed at a dose of 500 mg/m\^2, intravenous infusion, once per three weeks, 4 cycles in total

Also known as: One of the standard chemotherapy regimens

whole brain LDRT + ICI + intrathecal chemotherapy

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ≥ 18 years old and ≤ 75 years old;
• Patients with a definite diagnosis of leptomeningeal metastasis by cerebrospinal fluid cytology, or patients with clinical diagnosis combined with tumor history, neuroimaging, clinical manifestations, cerebrospinal fluid examination, etc.;
• Patients with a clear history of lung carcinoma, including histopathological diagnosis or a combination of cytopathology and imaging, and failure of standard treatment;
• Efficacy of extracranial lesions SD;
• Patients with no contraindications to craniocranial radiotherapy were judged by radiotherapy doctors. Subjects who agree to receive immunotherapy, Lumbar puncture, intrathecal chemotherapy, and radiotherapy;
• Expected survival ≥3 months, PS score ≤3;
• Agree to provide cerebrospinal fluid, blood and tissue samples for biomarker testing;
• The main organs function normally, no serious blood, heart, lung, liver, kidney, bone marrow and other functional abnormalities and immune deficiency diseases;
• One week before enrollment, bone marrow and liver and kidney function met the following criteria:
• ① Hemoglobin ≥80 g/L, neutrophils ≥1.5×10\^9/L and platelets ≥70×10\^9/L;
• ② Renal function: Cr≤ULN (upper limit of normal) × 1.5, endogenous creatinine clearance (Ccr)≥55 ml/min; Liver function: total bilirubin ≤ULN × 1.5; ALT, AST≤ULN × 2.5; (In case of liver metastasis, total bilirubin should not be higher than 3 times the upper normal limit, and transaminase should not be higher than 5 times the upper normal limit);
• The fertile women agreed to use contraception during the study period and for 6 months after the study ended; Patients who tested negative for a serum or urine pregnancy test within 7 days prior to joining the study and were not breastfed; Men who agreed to use contraception during the study period and for 6 months after the study ended

You may not qualify if:

• Active autoimmune disease or history of autoimmune diseases;
• Congenital or acquired immunodeficiency;
• Uncontrolled cardiac clinical symptoms or diseases;
• Severe infection or severe comorbidities, such as bleeding peptic ulcer, ileus, heart failure, renal failure, or poorly controlled diabetes;
• History of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation;
• Other systemic malignancies within the last 5 years;
• Allergy to any test drug;
• Pregnant and lactating women, subjects with reproductive capacity are unwilling to take effective contraceptive measures.

Sponsors & Collaborators

• Sichuan University: lead

Study Sites (1)

West China Hospital, Sichuan University

Chengdu, Sichuan, 610041, China

RECRUITING

Related Publications (10)

• Cao M, Chen W. Epidemiology of lung cancer in China. Thorac Cancer. 2019 Jan;10(1):3-7. doi: 10.1111/1759-7714.12916. Epub 2018 Nov 28.

  PMID: 30485694 BACKGROUND

• Clarke JL, Perez HR, Jacks LM, Panageas KS, Deangelis LM. Leptomeningeal metastases in the MRI era. Neurology. 2010 May 4;74(18):1449-54. doi: 10.1212/WNL.0b013e3181dc1a69.

  PMID: 20439847 BACKGROUND

• Remon J, Le Rhun E, Besse B. Leptomeningeal carcinomatosis in non-small cell lung cancer patients: A continuing challenge in the personalized treatment era. Cancer Treat Rev. 2017 Feb;53:128-137. doi: 10.1016/j.ctrv.2016.12.006. Epub 2016 Dec 30.

  PMID: 28110254 BACKGROUND

• Gleissner B, Chamberlain MC. Neoplastic meningitis. Lancet Neurol. 2006 May;5(5):443-52. doi: 10.1016/S1474-4422(06)70443-4.

  PMID: 16632315 BACKGROUND

• Cheng H, Perez-Soler R. Leptomeningeal metastases in non-small-cell lung cancer. Lancet Oncol. 2018 Jan;19(1):e43-e55. doi: 10.1016/S1470-2045(17)30689-7.

  PMID: 29304362 BACKGROUND

• Le Rhun E, Weller M, van den Bent M, Brandsma D, Furtner J, Ruda R, Schadendorf D, Seoane J, Tonn JC, Wesseling P, Wick W, Minniti G, Peters S, Curigliano G, Preusser M; EANO Guidelines Committee and ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Leptomeningeal metastasis from solid tumours: EANO-ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. ESMO Open. 2023 Oct;8(5):101624. doi: 10.1016/j.esmoop.2023.101624. Epub 2023 Sep 19.

  PMID: 37863528 BACKGROUND

• Chamberlain M, Junck L, Brandsma D, Soffietti R, Ruda R, Raizer J, Boogerd W, Taillibert S, Groves MD, Le Rhun E, Walker J, van den Bent M, Wen PY, Jaeckle KA. Leptomeningeal metastases: a RANO proposal for response criteria. Neuro Oncol. 2017 Apr 1;19(4):484-492. doi: 10.1093/neuonc/now183.

  PMID: 28039364 BACKGROUND

• Yin K, Li YS, Zheng MM, Jiang BY, Li WF, Yang JJ, Tu HY, Zhou Q, Zhong WZ, Yang XN, Chen HJ, Yan HH, Li LL, Wu YL, Zhang XC. A molecular graded prognostic assessment (molGPA) model specific for estimating survival in lung cancer patients with leptomeningeal metastases. Lung Cancer. 2019 May;131:134-138. doi: 10.1016/j.lungcan.2019.03.015. Epub 2019 Mar 18.

  PMID: 31027690 BACKGROUND

• Wang Y, Yang X, Li NJ, Xue JX. Leptomeningeal metastases in non-small cell lung cancer: Diagnosis and treatment. Lung Cancer. 2022 Dec;174:1-13. doi: 10.1016/j.lungcan.2022.09.013. Epub 2022 Oct 1.

  PMID: 36206679 BACKGROUND

• Thai K, Prat A. CNS therapeutics: Immune cells break the barriers. Sci Transl Med. 2023 Nov 8;15(721):eadh1150. doi: 10.1126/scitranslmed.adh1150. Epub 2023 Nov 8.

  PMID: 37939159 BACKGROUND

MeSH Terms

Conditions

Meningeal Carcinomatosis

Interventions

Radiotherapy; Pemetrexed; sintilimab; Immune Checkpoint Inhibitors; Drug Therapy

Condition Hierarchy (Ancestors)

Meningeal Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Therapeutics; Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Antineoplastic Agents, Immunological; Antineoplastic Agents; Therapeutic Uses

Study Officials

• You Lu, MD

  West China Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

You Lu, MD

CONTACT

18980601763; radyoulu@hotmali.com

Lisha Xiang, MD

CONTACT

13320943069; lishaxiang@foxmail.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chair of Department of Thoracic Cancer

Study Record Dates

• First Submitted: May 19, 2024
• First Posted: May 28, 2024
• Study Start: April 25, 2024
• Primary Completion: May 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: May 28, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)